This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 2.1 The Primary Aim WARCEF is a two-arm (1:1) double-blind randomized multicenter clinical trial. Its primary aim is to compare the effectiveness of warfarin and aspirin therapies in heart failure patients, while taking account of risk of hemorrhage. The primary null hypothesis is that in patients with EF [unreadable] 35%, there is no difference between warfarin (INR 2.5-3.0 with a target INR of 2.75) and aspirin (325 mg/day) therapies in time to the first to occur of ischemic stroke, intracerebral hemorrhage (ICH), or death. This is tested against the alternative hypothesis of a non-zero difference between these two therapies, at a = .05 two- sided, with power of 80% to detect a 17.82% hazard rate reduction (after appropriate allowance for crossover and loss to follow-up), with symmetrical stopping and decision rules. 3201 patients with 2-6 years of follow-up are required. Any of the three possible outcomes will be clinically important: + If warfarin is better, use of warfarin will be recommended. + If aspirin is better, use of aspirin will be recommended. + If the evidence is insufficient to declare either better, use of aspirin will be recommended, given its lower cost and easier administration. WARCEF is thus expected to be clinically decisive if it is completed with satisfactory power. 2.2 The Secondary Aims 1 The main secondary aim is to test the hypothesis of no difference in warfarin and aspirin therapies in time to the first to occur of, ischemic stroke, ICH, myocardial infarction (MI), heart failure (HF) hospitalization, or death. The additional secondary aims are to answer these questions: 2 Is warfarin or aspirin superior for reducing stroke (ischemic and hemorrhagic)? 3 Among women, is warfarin or aspirin therapy superior for reducing ischemic stroke, ICH, MI, heart failure hospitalization, or death? 4 Among African-Americans, is warfarin or aspirin therapy superior for reducing ischemic stroke, ICH, MI, heart failure hospitalization or death? 5 Does any relative risk or benefit of warfarin or aspirin for stroke, transient ischemic attack (TIA), or peripheral embolism depend on ejection fraction? 6 Does any relative risk or benefit of warfarin or aspirin depend on heart failure class (NYHA class)? 7 Does any relative risk or benefit of warfarin or aspirin depend on etiology of cardiac failure? 8 Do warfarin and aspirin differ in their effect on cognitive function? 9 Does warfarin have a larger risk reduction relative to aspirin in cardioembolic than other stroke subtypes? 10 Are cardioembolic infarcts more frequent in patients with non-ischemic than ischemic cardiac disease? 11 Are cardioembolic infarcts more frequent in women than in men? 12 Is mean cerebral infarct volume greater in patients with EF [unreadable] 20% than in patients with EF 20%? 2.3 The Tertiary aim is to combine the WARCEF data with that of the Warfarin Antiplatelet Trial in Chronic Heart Failure (WATCH) to provide more statistical power to address the secondary aims 1 through 7.